Progressive gait and balance difficulties, and associated falls, are among the most common levodopa resistant symptoms in Parkinson disease (PD), eventually occurring in nearly all patients. During the current funding period, U-M Udall Center research demonstrated a far more prominent, dynamic and multifaceted role for cholinergic signaling in PD gait abnormalities than previously appreciated. These insights position us to establish a systems neuroscience model of circuit interactions in gait by pursuing an interrelated and complementary set of clinical and basic studies, and to perform the first prospective assessment of cholinergic deficits as a biomarker of clinical heterogeneity in PD. Considerable data, including that developed during the current funding period, demonstrates that normal gait and posture depend on integration of sensory-attentional and motor information, and that cholinergic neurotransmission is vital for normal ?attentional-motor? interface at multiple CNS sites. These data support a novel, mechanistic model of attentional-motor interactions that will be tested with the studies proposed. Project I will dissect, in a rodent model, the role of cholinergic neurotransmission in detecting, transferring, and integrating attentional information as it traverses corticostriatal circuits. Opto- and chemo-genetic strategies will be used to test whether enhancing cortical or striatal cholinergic neurotransmission can reduce fall propensity in the ?Dual Lesion? (DL) rodent model of PD falls. Project II will employ the cholinergic PET ligand [18F]FEOBV in PD subjects to test the hypothesis that specific regional patterns of cholinergic dysfunction associate with distinct PD gait abnormalities, including falls and freezing of gait. Combined with Project I, this work has the potential to establish striatal cholinergic interneurons as an essential mediator of PD gait dysfunction. Project III will assess occipital cortical cholinergic denervation in PD subjects as an early, pathologic biomarker of later gait and cognitive decline. Projects II and III will take advantage of the uniquely valuable PD subject cohort established during the original funding period, and together constitute a first step toward the development of novel PD stratification tools. The U-M Udall Center will collaborate with members of the Pacific and University of Rochester Udall Centers, and be supported by Administrative, Clinical Resource, Neuroimaging Resource and Biostatistics and Data Management Cores. The Administrative Core is strongly committed to and will direct education of PD researchers, PD patients, and their families. Together, our innovative approaches will advance the goal of the NINDS Udall Centers of Excellence program to ?define the causes of and discover improved treatments for PD.? No other current Udall Center is focused on gait and postural abnormalities in PD, on cholinergic deficits, or on use of a pathological biomarker to define PD subgroups. The proposed U-M Udall Center will continue to play a unique and important role within the Udall Centers program.